EP1999111B1 - Monozyklische und bizyklische himbacin-derivate als thrombin-rezeptor-antagonisten - Google Patents
Monozyklische und bizyklische himbacin-derivate als thrombin-rezeptor-antagonisten Download PDFInfo
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- EP1999111B1 EP1999111B1 EP07754070.6A EP07754070A EP1999111B1 EP 1999111 B1 EP1999111 B1 EP 1999111B1 EP 07754070 A EP07754070 A EP 07754070A EP 1999111 B1 EP1999111 B1 EP 1999111B1
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Definitions
- the present invention relates to himbacine derivatives, which can be useful as thrombin receptor antagonists in the treatment of diseases associated with thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, cerebral ischemia, stroke, neurodegenerative diseases and cancer.
- thromboin receptor antagonists are also known as protease activated receptor-1 1 (PAR-1) antagonists.
- the compounds of the invention also can be useful as cannabinoid (CB 2 ) receptor inhibitors for the treatment of rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, diabetes, osteoporosis, renal ischemia, cerebral stroke, cerebral ischemia, nephritis, inflammatory disorders of the lungs and gastrointestinal tract, and respiratory tract disorders such as reversible airway obstruction, chronic asthma and bronchitis.
- CBD 2 cannabinoid
- Thrombin is known to have a variety of activities in different cell types. Thrombin receptors are known to be present in such cell types as human platelets, vascular smooth muscle cells, endothelial cells and fibroblasts. It is therefore expected that thrombin receptor antagonists will be useful in the treatment of thrombotic, inflammatory, atherosclerotic and fibroproliferative disorders, as well as other disorders in which thrombin and its receptor play a pathological role.
- Thrombin receptor antagonist peptides have been identified based on structure-activity studies involving substitutions of amino acids on thrombin receptors. In Bernatowicz et al., J. Med. Chem., 39 (1996), p. 4879-4887 , tetra- and pentapeptides are disclosed as being potent thrombin receptor antagonists, for example N-trans-cinnamoyl-p-fluoroPhe-p-guanidinoPhe-Leu-Arg-NH 2 and N-trans-cinnamoyl-p-fluoroPhe-p-guanidinoPhe-Leu-Arg-Arg-NH 2 . Peptide thrombin receptor antagonists are also disclosed in WO 94/03479, published February 17, 1994 .
- Cannabinoid receptors belong to the superfamily of G-protein coupled receptors. They are classified into the predominantly neuronal CB 1 receptors and the predominantly peripheral CB 2 receptors. These receptors exert their biological actions by modulating adenylate cyclase and Ca +2 and K + currents. While the effects of CB 1 receptors are principally associated with the central nervous system, CB 2 receptors are believed to have peripheral effects related to bronchial constriction, immunomodulation and inflammation.
- a selective CB 2 receptor binding agent is expected to have therapeutic utility in the control of diseases associated with rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, diabetes, osteoporosis, renal ischemia, cerebral stroke, cerebral ischemia, nephritis, inflammatory disorders of the lungs and gastrointestinal tract, and respiratory tract disorders such as reversible airway obstruction, chronic asthma and bronchitis ( R. G. Pertwee, Curr. Med. Chem. 6(8), (1999), 635 ; M. Bensaid, Molecular Pharmacology, 63 (4), (2003), 908 .).
- Himbacine a piperidine alkaloid of the formula has been identified as a muscarinic receptor antagonist.
- the total synthesis of (+)-himbacine is disclosed in Chackalamannil et al., J. Am. Chem. Soc., 118 (1996), p. 9812-9813 .
- Substituted tricyclic thrombin receptor antagonists are disclosed in US 6,063,847 , US 6,326,380 and U.S. Serial Nos. 09/880222 ( WO 01/96330 ) and 10/271715 .
- the present invention relates to: a compound of the formula: or
- compositions comprising at least one of the above compounds and at least one pharmaceutically acceptable carrier are also provided.
- Thrombin receptor antagonists also known as PAR-1 antagonists, or as cannabinoid (CB 2 ) receptor antagonists.
- Thrombin receptor antagonist compounds of the present invention can have anti-thrombotic, anti-platelet aggregation, anti-atherosclerotic, anti-restenotic anticoagulant, and/or anti-inflammatory activity.
- CB 2 receptor inhibitor compounds of the present invention can be useful for the treatment of rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, diabetes, osteoporosis, renal ischemia, cerebral stroke, cerebral ischemia, nephritis, inflammatory disorders of the lungs and gastrointestinal tract, and respiratory tract disorders such as reversible airway obstruction, chronic asthma and bronchitis.
- Compounds of the invention can be useful for the treatment of thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, angiogenesis related disorders, arrhythmia, a cardiovascular or circulatory disease or condition, heart failure, acute coronary syndrome (ACS), myocardial infarction, glomerulonephritis, thrombotic stroke, thromboembolytic stroke, peripheral vascular diseases, deep vein thrombosis, venous thromboembolism, a cardiovascular disease associated with hormone replacement therapy, disseminated intravascular coagulation syndrome, cerebral infarction, migraine, erectile dysfunction, rheumatoid arthritis, rheumatism, astrogliosis, a fibrotic disorder of the liver, kidney, lung or intestinal tract, systemic lupus erythematosus, multiple sclerosis, osteoporosis, renal disease, acute renal failure, chronic renal failure, renal vascular homeostasis, renal ischemia, bladder inflammation, diabetes, diabet
- compounds of the present invention are used to treat acute coronary syndrome, myocardial infarction or thrombotic stroke.
- Compounds of the present invention can also be used in a method to treat or prevent a condition associated with cardiopulmonary bypass surgery (CPB) comprising administering an effective amount of at least one thrombin receptor antagonist to a subject of said surgery.
- CPB surgery includes coronary artery bypass surgery (CABG), cardiac valvular repair and replacement surgery, pericardial and aortic repair surgeries.
- CABG surgery includes coronary artery bypass surgery (CABG), cardiac valvular repair and replacement surgery, pericardial and aortic repair surgeries.
- CABG coronary artery bypass surgery
- the present invention relates to a method of treating or preventing a condition associated with CABG surgery comprising administering an effective amount of at least one thrombin receptor antagonist to a subject of said surgery.
- the conditions associated with CABG are selected from the group consisting of: bleeding; thrombotic vascular events such as thrombosis, restenosis; vein graft failure; artery graft failure; atherosclerosis, angina pectoris; myocardial ischemia; acute coronary syndrome myocardial infarction; heart failure; arrhythmia; hypertension; transient ischemic attack; cerebral function impairment; thromboembolic stroke; cerebral ischemia; cerebral infarction; thrombophlebitis; deep vein thrombosis; and, peripheral vascular disease.
- thrombotic vascular events such as thrombosis, restenosis; vein graft failure; artery graft failure; atherosclerosis, angina pectoris; myocardial ischemia; acute coronary syndrome myocardial infarction; heart failure; arrhythmia; hypertension; transient ischemic attack; cerebral function impairment; thromboembolic stroke; cerebral ischemia; cerebral infarction; thromboph
- compounds of the present invention can be useful in a method for treating and/or preventing radiation- and/or chemical-induced toxicity in non-malignant tissue in a patient comprising administering a therapeutically effective amount of such a compound.
- the radiation- and/or chemical-induced toxicity is one or more of intestinal fibrosis, pneumonitis, and mucositis.
- the radiation- and/or chemical-induced toxicity is intestinal fibrosis.
- the radiation- and/or chemical-induced toxicity is oral mucositis.
- the radiation- and/or chemical-induced toxicity is intestinal mucositis, intestinal fibrosis, intestinal radiation syndrome, or pathophysiological manifestations of intestinal radiation exposure.
- the present compounds are also useful in methods for reducing structural radiation injury in a patient that will be exposed, is concurrently exposed, or was exposed to radiation and/or chemical toxicity, comprising administering a therapeutically effective amount of such a compound.
- the compounds are also useful in methods for reducing inflammation in a patient that will be exposed, is concurrently exposed, or was exposed to radiation and/or chemical toxicity, comprising administering a therapeutically effective amount of such a compound.
- the present compounds are also useful in methods for adverse tissue remodeling in a patient that will be exposed, is concurrently exposed, or was exposed to radiation and/or chemical toxicity, comprising administering a therapeutically effective amount of such a compound.
- the present compounds are also useful in methods for reducing fibroproliferative tissue effects in a patient that will be exposed, is concurrently exposed, or was exposed to radiation and/or chemical toxicity, comprising administering a therapeutically effective amount of such a compound.
- the present compounds are also useful in methods for treating a cell proliferative disorder in a patient suffering therefrom comprising administering a therapeutically effective amount of such a compound.
- the cell proliferative disorder is pancreatic cancer, glioma, ovarian cancer, colorectal and/or colon cancer, breast cancer, prostate cancer, thyroid cancer, lung cancer, melanoma, or stomach cancer.
- the glioma is an anaplastic astrocytoma.
- the glioma is a glioblastoma multiforme.
- the term inflammatory disease or condition includes irritable bowel syndrome, Crohn's disease, nephritis or a radiation- or chemotherapy- induced proliferative or inflammatory disorder of the gastrointestinal tract, lung, urinary bladder, gastrointestinal tract or other organ.
- respiratory tract disease or condition includes reversible airway obstruction, asthma, chronic asthma, bronchitis or chronic airways disease.
- Cancer includes renal cell carcinoma or an angiogenesis related disorder.
- Neurodegenerative disease includes Parkinson's disease, amyotropic lateral sclerosis, Aizheimer's disease, Huntington's disease or Wilson's disease.
- Certain embodiments of this invention also relate to the above compounds for use in combination with one or more additional agents for the treatment of thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, angiogenesis related disorders, arrhythmia, a cardiovascular or circulatory disease or condition, heart failure, acute coronary syndrome (ACS), myocardial infarction, glomerulonephritis, thrombotic stroke, thromboembolytic stroke, peripheral vascular diseases, deep vein thrombosis, venous thromboembolism, a cardiovascular disease associated with hormone replacement therapy, disseminated intravascular coagulation syndrome, cerebral infarction, migraine, erectile dysfunction, rheumatoid arthritis, rheumatism, astrogliosis, a fibrotic disorder of the liver, kidney, lung or intestinal tract, systemic lupus erythematosus, multiple sclerosis, osteoporosis, renal disease, acute renal failure, chronic renal failure, renal vascular homeostas
- the present invention includes administering to a patient in need of such treatment an effective amount of a combination of one or more of the above compounds and one or more radiation-response modifiers selected from the group consisting of KepivanceTM (palifermin), L-glutamine, teduglutide, sucralfate mouth rinses, iseganan, lactoferrin, mesna and trefoil factor.
- KepivanceTM palifermin
- L-glutamine L-glutamine
- teduglutide teduglutide
- sucralfate mouth rinses iseganan
- lactoferrin lactoferrin
- mesna and trefoil factor trefoil factor
- the present invention includes administering to a patient in need of such treatment an effective amount of a combination of one or more of the above compounds and another antineoplastic agent.
- the other antineoplastic agent is temozolomide and the cell proliferative disorder is glioma.
- the other antineoplastic agent is interferon and the cell proliferative disorder is melanoma.
- the other antineoplastic agent is PEG-Intron (peginterferon alpha-2b) and the cell proliferative disorder is melanoma.
- compositions comprising a therapeutically effective amount of a combination of at least one of the above compounds and at least one additional cardiovascular agent in a pharmaceutically acceptable carrier are also provided.
- compositions comprising a therapeutically effective amount of a combination of at least one of the above compounds and a radiation-response modifier in a pharmaceutically acceptable carrier are also provided.
- Pharmaceutical compositons comprising a therapeutically effective amount of a combination of at least one of the above compounds and an antineoplastic agent in a pharmaceutically acceptable carrier are also provided.
- combination of the invention can be provided as a kit comprising in a single package at least one of the above compounds in a pharmaceutical composition, and at least one separate pharmaceutical composition comprising a cardiovascular agent.
- the present invention provides a compound of the Formula: or R 9 , R 10 and R 11 are H.
- purified refers to the physical state of said compound after being isolated from a synthetic process (e.g. from a reaction mixture), or natural source or combination thereof.
- purified refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan (e.g., chromatography, recrystallization and the like), in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.
- composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
- Prodrugs, solvates, and co-crystals of the compounds of the invention are also contemplated herein.
- a discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series , and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press .
- the term "prodrug” means a compound (e.g, a drug precursor) that is transformed in vivo to yield a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate of the compound.
- the transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood.
- mechanisms e.g., by metabolic or chemical processes
- prodrugs are provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987 .
- a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (C 1 -C 6 )alkanoyloxymethyl, 1-((C 1 -C 6 )alkanoyloxy)ethyl, 1-methyl-1-((C 1 -C 6 )alkanoyloxy)ethyl, (C 1 -C 6 )alkoxycarbonyloxymethyl, N-(C 1 -C 6 )alkoxycarbonylaminomethyl, succinoyl, (C 1 -C 6 )alkanoyl.
- a group such as, for example, (C 1 -C 6 )alkanoyloxymethyl, 1-((C 1 -C 6 )alkanoyloxy)ethyl, 1-methyl-1-((C 1 -C 6 )alkanoyloxy)ethyl, (C 1 -C 6 )alkoxycarbonyloxymethyl, N-(C
- each ⁇ -aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH) 2 , -P(O)(O(C 1 -C 6 )alkyl) 2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate), and the like.
- One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
- “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanotates, and the like.
- “Hydrate” is a solvate wherein the solvent molecule is H 2 O.
- One or more compounds of the invention may optionally be converted to a solvate.
- Preparation of solvates is generally known.
- M. Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004 ) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water.
- Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et al, AAPS PharmSciTech., 5(1), article 12 (2004 ); and A. L. Bingham et al, Chem. Commun., 603-604 (2001 ).
- a typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods.
- Analytical techniques such as, for example I. R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).
- a co-crystal is a crystalline superstructure formed by combining an active pharmaceutical intermediate with an inert molecule that produces crystallinity to the combined form.
- Co-crystals are often made between a dicarboxlyic acid such as fumaric acid, succinic acid etc. and a basic amine such as the one represented by compound I of this invention in different proportions depending on the nature of the co-crystal. ( Rmenar, J. F. et. al. J Am. Chem. Soc. 2003, 125, 8455 ).
- Effective amount or “therapeutically effective amount” is meant to describe an amount of compound or a composition of the present invention effective in inhibiting the above-noted diseases and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect.
- salts can form salts which are also within the scope of this invention.
- Reference to a compound of the present invention is understood to include reference to salts thereof, unless otherwise indicated.
- the term "salt(s)" denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases.
- zwitterions inner salts may be formed and are included within the term "salt(s)" as used herein.
- Salts of the compounds of the Formula I may be formed, for example, by reacting a compound of Formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
- Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like.
- Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like.
- Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g.
- dimethyl, diethyl, and dibutyl sulfates dimethyl, diethyl, and dibutyl sulfates
- long chain halides e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides
- aralkyl halides e.g. benzyl and phenethyl bromides
- esters of the present compounds include the following groups: (1) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n-propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted with, for example, halogen, C 1-4 alkyl, or C 1-4 alkoxy or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl); (4) phosphoric acid
- the present compounds may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.
- the present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
- isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
- Certain isotopically-labelled compounds of the present invention are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may referred in some circumstances.
- Isotopically labelled compounds of this invention can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples hereinbelow, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent
- the compounds according to the invention have pharmacological properties; in particular, these compounds can be nor-seco himbacine derivatives useful as thrombin receptor antagonists.
- Compounds of the invention have at least one asymmetrical carbon atom and therefore all isomers including enantiomers, stereoisomers, rotamers, tautomers and racemates of the present compounds (where they exist) are contemplated as being part of this invention.
- the invention includes d and I isomers in both pure form and in admixture, including racemic mixtures.
- Isomers can be prepared using conventional techniques, either by reacting optically pure or optically enriched starting materials or by separating isomers of a compound of the present invention. Isomers may also include geometric isomers, e.g ., when a double bond is present. Polymorphous forms of the present compounds, whether crystalline or amorphous, also are contemplated as being part of this invention.
- 11b , 11c and 11d were prepared by using the corresponding boronic acids. Also, 11e was prepared in a similar fashion, except, (2-cyanophenyl)boronic acid 2,2-dimethylpropanediol-1,3 cyclic ester was used in place of 2-cyanophenylboronic acid.
- Additional agents that can be used in combination with the novel compounds of this invention include drugs that are useful in treating thrombosis-related diseases including thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, angiogenesis related disorders, arrhythmia, a cardiovascular or circulatory disease or condition, heart failure, myocardial infarction, glomerulonephritis, thrombotic stroke, thromboembolytic stroke, peripheral vascular diseases, cerebral ischemia, rheumatoid arthritis, rheumatism, astrogliosis, a fibrotic disorder of the liver, kidney, lung or intestinal tract, systemic lupus erythematosus, multiple sclerosis, osteoporosis, glomerulonephritis, renal disease, acute renal failure, chronic renal failure, renal thrombosis-related diseases including thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, angiogenesis related disorders, arrhythmia, a cardiovascular
- Suitable cardiovascular agents are selected from the group consisting of thromboxane A2 biosynthesis inhibitors; thromboxane antagonists; adenosine diphosphate inhibitors; cyclooxygenase inhibitors; angiotensin antagonists; endothelin antagonists; phosphodiesterase inhibitors; angiotensin converting enzyme inhibitors; neutral endopeptidase inhibitors; anticoagulants; diuretics; platelet aggregation inhibitors; and GP IIb/IIIa antagonists.
- Preferred types of drugs for use in combination with the novel compounds of this invention are thromboxane A2 biosynthesis inhibitors, GP IIb/IIIa antagonists, thromboxane antagonists, adenosine diphosphate inhibitors, cyclooxygenase inhibitors, angiotensin antagonists, endothelin antagonists, angiotensin converting enzyme inhibitors, neutral endopeptidase inhibitors, anticoagulants, diuretics, and platelet aggregation inhibitors.
- suitable cardiovascular agents are selected from the group consisting of aspirin, seratrodast, picotamide and ramatroban, clopidogrel, meloxicam, rofecoxib, celecoxib, valsartan, telmisartan, candesartran, irbesartran, losartan, eprosartan, tezosentan, milrinoone, enoximone, captopril, enalapril, enaliprilat, spirapril, quinapril, perindopril, ramipril, fosinopril, trandolapril, lisinopril, moexipril, benazapril, candoxatril, ecadotril, ximelagatran, fondaparin, enoxaparin, chlorothiazide, hydrochlorothiazide, ethacrynic acid, furose
- Especially preferred for use in the combinations are aspirin, cangrelor, clopidogrel bisulfate, parsugrel and fragmin.
- the two active components may be co-administered simultaneously or sequentially, or a single pharmaceutical composition comprising a compound of the present invention and another agent in a pharmaceutically acceptable carrier can be administered.
- the components of the combination can be administered individually or together in any conventional dosage form such as capsule, tablet, powder, cachet, suspension, solution, suppository, nasal spray, etc.
- the dosage of the additional agent can be determined from published material, and may range from 1 to 1000 mg per dose.
- the term "at least one compound of the present invention” means that one to three different compounds defined in claim 1 may be used in a pharmaceutical composition or method of treatment. Preferably one such compound is used.
- the term “one or more additional cardiovascular agents” means that one to three additional drugs may be administered in combination with the present compound ; preferably, one additional compound is administered in combination with a compound of the present invention. The additional agents can be administered sequentially or simultaneously with reference to the compound of the present invention.
- inert, pharmaceutically acceptable carriers can be either solid or liquid.
- Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories.
- the powders and tablets may be comprised of from about 5 to about 95 percent active ingredient.
- Suitable solid carriers are known in the art, e.g. magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), The Science and Practice of Pharmacy, 20th Edition, (2000), Lippincott Williams & Wilkins, Baltimore, MD .
- Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.
- Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.
- a pharmaceutically acceptable carrier such as an inert compressed gas, e.g. nitrogen.
- solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration.
- liquid forms include solutions, suspensions and emulsions.
- the compounds of the invention may also be deliverable transdermally.
- the transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
- the compound is administered orally.
- the pharmaceutical preparation is in a unit dosage form.
- the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
- the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1 mg to about 150 mg, preferably from about 1 mg to about 75 mg, more preferably from about 1 mg to about 50 mg, according to the particular application.
- the actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.
- a typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 300 mg/day, preferably 1 mg/day to 75 mg/day, in two to four divided doses.
- kits comprising in a single package, one container comprising a compound of Formula I in a pharmaceutically acceptable carrier, and a separate container comprising another cardiovascular agent in a pharmaceutically acceptable carrier, with the compound of Formula I and the other agent being present in amounts such that the combination is therapeutically effective.
- a kit is advantageous for administering a combination when, for example, the components must be administered at different time intervals or when they are in different dosage forms.
- the activity of the compounds of the present invention can be determined by the following procedures.
- A(pF-F)R(ChA)(hR)(I 2 -Y)-NH 2 (1.03 mg) and 10% Pd/C (5.07 mg) were suspended in DMF (250 ⁇ l) and diisopropylethylamine (10 ⁇ l).
- the vessel was attached to the tritium line, frozen in liquid nitrogen and evacuated.
- Tritium gas (342 mCi) was then added to the flask, which was stirred at room temperature for 2 hours.
- the excess tritium was removed and the reacted peptide solution was diluted with DMF (0.5 ml) and filtered to remove the catalyst.
- the collected DMF solution of the crude peptide was diluted with water and freeze dried to remove the labile tritium.
- the solid peptide was redissolved in water and the freeze drying process repeated.
- the tritiated peptide [ 3 H]haTRAP) was dissolved in 0.5 ml of 0.1% aqueous TFA and purified by HPLC using the following conditions: column, VydacTM C18, 25 cm x 9.4 mm I.D.; mobile phase, (A) 0.1 % TFA in water, (B) 0.1% TFA in CH 3 CN; gradient, (A/B) from 100/0 to 40/60 over 30 min; flow rate, 5 ml /min; detection, UV at 215 nm.
- the radiochemical purity of [ 3 H]haTRAP was 99% as analyzed by HPLC. A batch of 14.9 mCi at a specific activity of 18.4 Ci/mmol was obtained.
- Platelet membranes were prepared using a modification of the method of Natarajan et al . ( Natarajan et al, Int. J. Peptide Protein Res. 45:145-151 (1995 )) from 20 units of platelet concentrates obtained from the North Jersey Blood Center (East Orange, NJ) within 48 hours of collection. All steps were carried out at 4° C under approved biohazard safety conditions. Platelets were centrifuged at 100 x g for 20 minutes at 4° C to remove red cells. The supernatants were decanted and centrifuged at 3000 ⁇ g for 15 minutes to pellet platelets.
- Platelets were re-suspended in 10 mM Tris-HCl, pH 7.5, 150 mM NaCl, 5 mM EDTA, to a total volume of 200 ml and centrifuged at 4400 x g for 10 minutes. This step was repeated two additional times. Platelets were re-suspended in 5 mM Tris-HCl, pH 7.5, 5 mM EDTA to a final volume of approximately 30 ml and were homogenized with 20 strokes in a DounceTM homogenizer.
- Membranes were pelleted at 41,000 x g, re-suspended in 40-50 ml 20 mM Tris-HCl, pH 7.5, 1 mM EDTA, 0.1 mM dithiothreitol, and 10 ml aliquots were frozen in liquid N 2 and stored at - 80° C. To complete membrane preparation, aliquots were thawed, pooled, and homogenized with 5 strokes of a Dounce homogenizer.
- Membranes were pelleted and washed 3 times in 10 mM triethanolamine-HCl, pH 7.4, 5 mM EDTA, and re-suspended in 20-25 ml 50 mM Tris-HCl, pH 7.5, 10 mM MgCl 2 , 1 mM EGTA, and 1 % DMSO. Aliquots of membranes were frozen in liquid N 2 and stored at -80° C. Membranes were stable for at least 3 months. 20 units of platelet concentrates typically yielded 250 mg of membrane protein. Protein concentration was determined by a Lowry assay ( Lowry et al., J. Biol. Chem., 193:265-275 (1951 )).
- Thrombin receptor antagonists were screened using a modification of the thrombin receptor radioligand binding assay of Ahn et al . ( Ahn et al., Mol. Pharmacol., 51:350-356 (1997 )). The assay was performed in 96 well Nunc plates (Cat. No. 269620) at a final assay volume of 200 ⁇ l. Platelet membranes and [ 3 H]haTRAP were diluted to 0.4 mg/ml and 22.2 nM, respectively, in binding buffer (50 mM Tris-HCl, pH 7.5, 10 mM MgCl 2 , 1 mM EGTA, 0.1% BSA).
- A(pF-F)R(ChA)(hR)Y-NH 2 and A(pF-F)R(ChA)(hR)(I 2 -Y)-NH 2 were custom synthesized by AnaSpec Inc. (San Jose, CA). The purity of these peptides was >95%. Tritium gas (97%) was purchased from EG&G Mound, Miamisburg, Ohio. The gas was subsequently loaded and stored on an IN/US Systems Inc. Trisorber. MicroScintTM 20 scintillation cocktail was obtained from Packard Instrument Co.
- Binding to the human cannabinoid CB 2 receptor was carried out using the procedure of Showalter, et al. (1996, J. Pharmacol Exp Ther. 278(3), 989-99 ), with minor modifications. All assays were carried out in a final volume of 100 ul. Test compounds were re-suspended to 10 mM in DMSO, then serially diluted in 50 mM Tris, pH 7.1, 3 mM MgCl 2 , 1 mM EDTA, 50% DMSO. Aliquots (10 ul) of each diluted sample were then transferred into individual wells of a 96-well microtiter plate.
- membranes were harvested by filtration through pretreated (0.5% polyethylenimine; Sigma P-3143) GF-C filter plates (Unifilter-96, Packard) using a TomTecTM Mach 3U 96-well cell harvester (Hamden, Ct). Plates were washed 10 times in 100 ul binding buffer, and the membranes allowed to air dry. Radioactivity on membranes was quantitated following addition of Packard OmniscintTM 20 scintillation fluid using a TopCountTM NXT Microplate Scintillation and Luminescence Counter (Packard, Meriden, Ct). Non-linear regression analysis was performed using PrismTM 20b. (GraphPad Software, San Diego, Ca).
Claims (21)
- Eine pharmazeutische Zusammensetzung, umfassend eine wirksame Menge von wenigstens einer Verbindung nach Anspruch 1 und einen pharmazeutisch annehmbaren Träger.
- Eine Verbindung gemäß Anspruch 1 zur Verwendung bei einem Verfahren zur Inhibierung von Thrombinrezeptoren, umfassend die Verabreichung einer wirksamen Menge von wenigstens einer Verbindung nach Anspruch 1 an einen Säuger, der eine solche Behandlung benötigt.
- Eine Verbindung gemäß Anspruch 1 zur Verwendung bei einem Verfahren zur Behandlung von Thrombose, Atherosklerose, Restenose, Hypertonie, Angina pectoris, angiogenesebedingten Störungen, Arrhythmie, einer/eines Herz-Kreislauf- oder Kreislauferkrankung oder -zustands, Herzversagen, akutem Koronarsyndrom, Myokardinfarkt, Glomerulonephritis, thrombotischem Schlaganfall, thromboembolischem Schlaganfall, peripheren vaskulären Erkrankungen, tiefer Venenthrombose, venöser Thromboembolie, einer kardiovaskulären Erkrankung in Verbindung mit Hormonersatztherapie, disseminierter intravasaler Gerinnung, Zerebralinfarkt, Migräne, erektiler Dysfunktion, rheumatoider Arthritis, Rheumatismus, Astrogliose, einer fibrotischen Störung der Leber, Niere, Lunge oder des Darmtrakts, systemischem Lupus erythematodes, Multipler Sklerose, Osteoporose, einer Nierenerkrankung, akutem Nierenversagen, chronischem Nierenversagen, renaler vaskulärer Homöostase, renaler Ischämie, Blasenentzündung, Diabetes, diabetischer Neuropathie, Hirnschlag, zerebraler Ischämie, Nephritis, Krebs, Melanom, Nierenzellkarzinom, Neuropathie, malignen Tumoren, neurodegenerativen und/oder neurotoxischen Erkrankungen, Zuständen oder Verletzungen, Alzheimer-Krankheit, einer Entzündungserkrankung oder einem Entzündungszustand, Asthma, Glaukom, Makuladegeneration, Psoriasis, Endotheldysfunktionsstörungen der Leber, Niere oder Lunge, Entzündungserkrankungen der Lungen und des Magen-Darm-Trakts, Erkrankungen oder Zustände der Atemwege, Strahlenfibrose, Endotheldysfunktion, parodontalen Erkrankungen oder Wunden oder einer Rückenmarksverletzung oder einem Symptom oder einer Folge davon, umfassend die Verabreichung einer wirksamen Menge von wenigstens einer Verbindung nach Anspruch 1 an einen Säuger, der eine solche Behandlung benötigt.
- Die Verbindung zur Verwendung gemäß Anspruch 4, wobei die Entzündungserkrankung oder der Entzündungszustand entzündliche Darmerkrankung, Morbus Cohn, Nephritis oder eine durch Strahlung oder Chemotherapie hervorgerufene proliferative oder entzündliche Störung des Magen-Darm-Trakts, der Lunge, der Harnblase, des Magen-Darm-Trakts oder eines anderen Organs ist.
- Die Verbindung zur Verwendung gemäß Anspruch 4, wobei die Atemwegserkrankung oder der Atemwegszustand reversible Obstruktion der Atemwege, Asthma, chronisches Asthma, Bronchitis oder chronische Atemwegserkrankung ist.
- Die Verbindung zur Verwendung gemäß Anspruch 4, wobei der Krebs Nierenzellkarzinom, oder eine angiogenesebedingte Störung ist.
- Die Verbindung zur Verwendung gemäß Anspruch 4, wobei die neurodegenerative Erkrankung Parkinson-Krankheit, amyotrophe Lateralsklerose, Alzheimer-Krankheit, Huntington-Krankheit oder Wilson-Krankheit ist.
- Die Verbindung zur Verwendung gemäß Anspruch 4, wobei das Verfahren ferner die Verabreichung von wenigstens zwei therapeutisch wirksamen Mitteln umfasst.
- Eine Verbindung gemäß Anspruch 1 zur Verwendung bei einem Verfahren zur Behandlung von Thrombose, Atherosklerose, Restenose, Hypertonie, Angina pectoris, angiogenesebedingten Störungen, Arrhythmie, einer/eines Herz-Kreislauf- oder Kreislauferkrankung oder -zustands, Herzversagen, akutem Koronarsyndrom, Myokardinfarkt, Glomerulonephritis, thrombotischem Schlaganfall, thromboembolischem Schlaganfall, peripheren vaskulären Erkrankungen, tiefer Venenthrombose, venöser Thromboembolie, einer kardiovaskulären Erkrankung in Verbindung mit Hormonersatztherapie, disseminierter intravasaler Gerinnung, Zerebralinfarkt, Migräne, erektiler Dysfunktion, rheumatoider Arthritis, Rheumatismus, Astrogliose, einer fibrotischen Störung der Leber, Niere, Lunge oder des Darmtrakts, systemischem Lupus erythematodes, Multipler Sklerose, Osteoporose einer Nierenerkrankung, akutem Nierenversagen, chronischem Nierenversagen, renaler vaskulärer Homöostase, renaler Ischämie, Blasenentzündung, Diabetes, diabetischer Neuropathie, Hirnschlag, zerebraler Ischämie, Nephritis, Krebs, Melanom, Nierenzellkarzinom, Neuropathie, malignen Tumoren, neurodegenerativen und/oder neurotoxischen Erkrankungen, Zuständen oder Verletzungen, Alzheimer-Krankheit, einer Entzündungserkrankung oder einem Entzündungszustand, Asthma, Glaukom, Makuladegeneration, Psoriasis, Endotheldysfunktionsstörungen der Leber, Niere oder Lunge, Entzündungserkrankungen der Lungen und des Magen-Darm-Trakts, Erkrankungen oder Zustände der Atemwege, Strahlenfibrose, Endotheldysfunktion, parodontalen Erkrankungen oder Wunden oder einer Rückenmarksverletzung oder einem Symptom oder einer Folge davon, umfassend die Verabreichung einer wirksamen Menge einer Verbindung nach Anspruch 1 in Kombination mit wenigstens einem zusätzlichen kardiovaskulären Mittel an einen Säuger, der eine solche Behandlung benötigt.
- Die Verbindung zur Verwendung gemäß Anspruch 10, wobei das oder die zusätzliche(n) kardiovaskuläre(n) Mittel ausgewählt ist/sind aus der Gruppe, bestehend aus Thromboxan-A2-Biosynthese-Inhibitoren, GP-IIb/IIIa-Antagonisten, Thromboxan-Antagonisten, Adenosindiphosphat-Inhibitoren, Cyclooxygenase-Inhibitoren, Angiotensin-Antagonisten, Endothelin-Antagonisten, Angiotensinkonversionsenzym-Inhibitoren, Inhibitoren der neutralen Endopeptidase, Antikoagulationsmitteln, Diuretika und Blutplättchenaggregationsinhibitoren.
- Die Verbindung zur Verwendung gemäß Anspruch 11, wobei das oder die zusätzliche(n) kardiovaskuläre(n) Mittel ausgewählt ist/sind aus der Gruppe, bestehend aus Aspirin, Cangrelor, Clopidogrel-Bisulfat, Parsugrel und Fragmin.
- Die Verbindung zur Verwendung gemäß Anspruch 12, wobei die zusätzlichen kardiovaskulären Mittel Aspirin und Clopidogrel-Bisulfat sind.
- Die Verbindung zur Verwendung gemäß Anspruch 12, wobei die zusätzlichen kardiovaskulären Mittel Aspirin und Parsugrel sind.
- Eine Verbindung gemäß Anspruch 1 zur Verwendung bei einem Verfahren zur Inhibierung von Cannabinoid-Rezeptoren, umfassend die Verabreichung einer wirksamen Menge von wenigstens einer Verbindung nach Anspruch 1 an einen Säuger, der eine solche Behandlung benötigt.
- Eine Verbindung gemäß Anspruch 1 zur Verwendung bei einem Verfahren zur Behandlung oder Prävention von durch Strahlung oder chemisch induzierter Toxizität in nichtmalignem Gewebe bei einem Patienten, umfassend die Verabreichung einer therapeutisch wirksamen Menge von wenigstens einer Verbindung nach Anspruch 1.
- Die Verbindung zur Verwendung gemäß Anspruch 16, wobei die durch Strahlung und/oder chemisch induzierte Toxizität eine oder mehrere aus intestinaler Fibrose, Pneumonitis, intestinaler Mukositis, oraler Mukositis, intestinalem Strahlensyndrom oder pathophysiologischen Manifestationen von intestinaler Strahlenexposition ist.
- Eine Verbindung gemäß Anspruch 1 zur Verwendung bei einem Verfahren zur Verringerung einer strukturellen Strahlenverletzung bei einem Patienten, der Strahlung und/oder chemischer Toxizität ausgesetzt sein wird, ausgesetzt ist oder ausgesetzt war; Verringerung einer Entzündung bei einem Patienten, der Strahlung und/oder chemischer Toxizität ausgesetzt sein wird, ausgesetzt ist oder ausgesetzt war; zur Umformung von negativ beeinflusstem Gewebe bei einem Patienten, der Strahlung und/oder chemischer Toxizität ausgesetzt sein wird, ausgesetzt ist oder ausgesetzt war; oder zur Verringerung fibroproliferativer Gewebeeffekte bei einem Patienten, der Strahlung und/oder chemischer Toxizität ausgesetzt sein wird, ausgesetzt ist oder ausgesetzt war; umfassend die Verabreichung einer therapeutisch wirksamen Menge von wenigstens einer Verbindung nach Anspruch 1.
- Eine Verbindung gemäß Anspruch 1 zur Verwendung bei einem Verfahren zur Behandlung einer zellproliferativen Erkrankung bei einem Patienten, der daran leidet, umfassend die Verabreichung einer therapeutisch wirksamen Menge von wenigstens einer Verbindung nach Anspruch 1.
- Die Verbindung zur Verwendung gemäß Anspruch 19, wobei die zellproliferative Erkrankung Bauchspeicheldrüsenkrebs, Gliom, Ovarialkarzinom, Kolorektalkarzinom, Kolonkarzinom, Brustkrebs, Prostatakrebs, Schilddrüsenkrebs, Lungenkrebs, Melanom oder Magenkrebs ist.
- Die Verbindung zur Verwendung gemäß Anspruch 20, wobei das Gliom ein anaplastisches Astrozytom oder ein Glioblastoma multiforme ist.
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US78696106P | 2006-03-29 | 2006-03-29 | |
PCT/US2007/007497 WO2007126771A2 (en) | 2006-03-29 | 2007-03-27 | Monocyclic and bicyclic himbacine derivatives useful as thrombin receptor antagonists |
Publications (2)
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EP1999111A2 EP1999111A2 (de) | 2008-12-10 |
EP1999111B1 true EP1999111B1 (de) | 2013-12-18 |
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EP07754070.6A Active EP1999111B1 (de) | 2006-03-29 | 2007-03-27 | Monozyklische und bizyklische himbacin-derivate als thrombin-rezeptor-antagonisten |
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US (1) | US7888377B2 (de) |
EP (1) | EP1999111B1 (de) |
JP (1) | JP2009534308A (de) |
KR (1) | KR20080104352A (de) |
CN (1) | CN101460463A (de) |
AR (1) | AR060095A1 (de) |
AU (1) | AU2007243657A1 (de) |
CA (1) | CA2647933A1 (de) |
MX (1) | MX2008012574A (de) |
TW (1) | TW200811107A (de) |
WO (1) | WO2007126771A2 (de) |
ZA (1) | ZA200808247B (de) |
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US8227412B2 (en) * | 2007-03-29 | 2012-07-24 | Tsopanoglou Nikos E | Bioactive parstatin peptides and methods of use |
WO2011128420A1 (de) | 2010-04-16 | 2011-10-20 | Sanofi | Pyridyl-vinyl-pyrazolo-chinoline als par1-inhibitoren |
PL2558465T3 (pl) | 2010-04-16 | 2015-05-29 | Sanofi Sa | Trycykliczne pirydylo-winylo-pirole jako inhibitory receptora aktywowanego proteazą 1 (PAR1) |
CA2833806A1 (en) * | 2011-04-28 | 2012-11-01 | Claire Mitchell | Method for treatment of macular degeneration by modulating p2y12 or p2x7 receptors |
WO2015013083A1 (en) * | 2013-07-22 | 2015-01-29 | Merck Sharp & Dohme Corp. | Co-crystal of the par-1 receptor antagonist vorapaxar and aspirin |
CN105777681B (zh) * | 2014-12-17 | 2019-03-01 | 博瑞生物医药(苏州)股份有限公司 | 喜巴辛类似物及其中间体的制备方法 |
CN105949116A (zh) * | 2016-06-08 | 2016-09-21 | 青岛理工大学 | 酰基哌嗪类化合物及其制备方法和用途 |
CN110559294A (zh) * | 2018-06-06 | 2019-12-13 | 杨仑 | 脂肪性肝病及其相关疾病的预防和治疗性药物 |
US20210395299A1 (en) * | 2018-10-29 | 2021-12-23 | Huahai Us Inc. | Novel dipeptide compounds and uses thereof |
CN110627710B (zh) * | 2019-09-29 | 2020-06-05 | 山东大学 | 一种新型par-1抑制剂及其制备方法和在预防和/或治疗血栓性疾病中的用途 |
TW202322824A (zh) | 2020-02-18 | 2023-06-16 | 美商基利科學股份有限公司 | 抗病毒化合物 |
CN111879949B (zh) * | 2020-08-05 | 2021-11-09 | 中国科学院昆明动物研究所 | 检测或调控乳铁蛋白表达量的物质在制备预防和/或治疗心脑血管疾病药物或试剂盒的应用 |
CN112759548B (zh) * | 2020-12-31 | 2021-11-02 | 山东大学 | 一种par-1抑制剂及其制备方法 |
CN117120444A (zh) | 2021-04-16 | 2023-11-24 | 吉利德科学公司 | 使用酰胺制备卡巴核苷的方法 |
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IL106197A (en) | 1992-07-30 | 1999-11-30 | Cor Therapeutics Inc | Agagonists for the rhombin receptors and pharmaceutical preparations containing them |
US6063847A (en) * | 1997-11-25 | 2000-05-16 | Schering Corporation | Thrombin receptor antagonists |
HUP0303081A3 (en) * | 2000-06-15 | 2009-03-30 | Schering Corp | Thrombin receptor antagonists, pharmaceutical compositions containing them and their use |
US7488742B2 (en) * | 2000-06-15 | 2009-02-10 | Schering Corporation | Thrombin receptor antagonists |
BR0213967A (pt) * | 2001-10-18 | 2005-08-30 | Schering Corp | Análogos de himbacina como antagonistas do receptor de trombina |
BRPI0409376A (pt) * | 2003-04-15 | 2006-04-25 | Inflazyme Pharm Ltd | derivados de indeno como agentes farmacêuticos |
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- 2007-03-27 AR ARP070101263A patent/AR060095A1/es not_active Application Discontinuation
- 2007-03-27 KR KR1020087023799A patent/KR20080104352A/ko not_active Application Discontinuation
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- 2007-03-27 MX MX2008012574A patent/MX2008012574A/es unknown
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- 2007-03-27 JP JP2009502927A patent/JP2009534308A/ja not_active Withdrawn
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JP2009534308A (ja) | 2009-09-24 |
US20070232635A1 (en) | 2007-10-04 |
WO2007126771A2 (en) | 2007-11-08 |
CN101460463A (zh) | 2009-06-17 |
TW200811107A (en) | 2008-03-01 |
EP1999111A2 (de) | 2008-12-10 |
ZA200808247B (en) | 2009-11-25 |
KR20080104352A (ko) | 2008-12-02 |
CA2647933A1 (en) | 2007-11-08 |
WO2007126771A3 (en) | 2007-12-21 |
AR060095A1 (es) | 2008-05-21 |
AU2007243657A1 (en) | 2007-11-08 |
US7888377B2 (en) | 2011-02-15 |
MX2008012574A (es) | 2008-10-10 |
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